Small Molecule Inhibitors of Alpha-Synuclein Assembly and Toxicity

Rapid Response Innovation Awards, 2009

Objective/Rationale:
We will test a novel drug candidate that blocks formation of the toxic aggregates of the protein alpha-synuclein, which are believed to cause Parkinson’s disease (PD). Our drug was discovered using a rationale approach and works by a novel mechanism. It has shown promising results in a pre-clinical model of Alzheimer’s disease and a fish model of PD. As a necessary step towards human clinical trials, we will now test the drug in a pre-clinical model of PD.Project Description:
The project has three goals: 1) to test the ability of the new drug to prevent and/or reverse the formation of the neurotoxic alpha-synuclein aggregates that are believed to cause PD; 2) to determine the pharmacologic profile of the drug; and 3) to study the drug’s mechanism of action. The mouse studies will be conducted in collaboration between the Bitan and Chesselet laboratories at UCLA using one of the most advanced pre-clinical models of PD available to date. Pharmacologic studies will be outsourced to a specialized Contract Research Organization. These studies will establish the best route of administration and the extent of penetration through the blood–brain barrier. The mechanistic studies will be performed using state-of-the-art biophysical techniques. The data will guide the biological studies and enable optimization of new generations of future drugs with improved characteristics.Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The project will establish the usefulness of a novel drug for PD by determining its efficacy in a relevant pre-clinical model, pharmacologic profile, and mechanism of action. These are necessary steps, which upon successful completion will be followed by behavioral studies and safety characterization towards initiation of human clinical trials.Anticipated Outcome:
We expect to establish an optimal route of administration and determine the optimal dose of the drug in mice. These findings later will be translated into use in humans. The studies will demonstrate the capability of the new drug to prevent and/or reverse the formation of the toxic alpha-synuclein aggregates (the human version of the protein) in mouse brain. The pharmacologic data will be necessary for the design of safety studies before the compound can be administered to humans.

FINAL OUTCOME

We have explored the use of a novel small-molecule inhibitor of alpha-synuclein aggregation and toxicity as a lead towards development of a disease-modifying drug for PD. We found that the compound, called CLR01, efficiently inhibits alpha-synuclein aggregation. Initial experiments in animal models show promising results and support the development of CLR01 towards human clinical trials.